Gold Nanoparticles - Department of Chemistry

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Nano Letters PERSPECTIVE Table 1. Examples of the Use of Bulk Gold in Clinical Practice in 1927. Although gold therapy proved to be ineffective for tuberculosis, a study by the Empire Rheumatism Council confirmed gold to be effective in RA, with Forestier showing beneficial results in RA patients in 1935. 5,7 Gold has since been used as a therapeutic agent to treat a wide variety of rheumatic diseases including psoriatic arthritis, 8 juvenile arthritis, and discoid lupus erythematosus; 9,10 however, its use has been largely superseded by newer drugs. Gold has also been used in several other areas of medicine including prostheses in dentistry 11 and ophthalmology, 12 gene delivery, 13 and gold coated coronary 14 and renal 15 stents, to name a few (Table 1). The Chemistry of Gold. Gold is a noble metal found in group 1B of the periodic table with an atomic number of 197. Gold can exist in a number of oxidation states: ( I), (0), (I), (II), (III), (IV), and (V), however, only gold(0), (I), and (III) are stable in aqueous solution. Hence, in vivo, gold exists in equilibrium between its metallic ground state (gold(0)) and its oxidized states (gold(I) or gold(III)). 6 Metallic gold does not oxidize or burn in air, even when heated, and has been shown to be inert to strong alkalis and acids thereby making it one of the least chemically reactive metals known to man. 11 In contrast, gold(I) and (III) are unstable with respect to gold(0), with gold(III) being a strong oxidizing agent which is reduced to gold(I) by biologically occurring reductants such as thiols. 5 As gold(I) preferentially reacts with S-donors, rather than O- and N- donors, it can be stabilized by thiolate ligands. These resulting gold thiol compounds then undergo biological ligand exchange reactions which account, in part, for their pharmacological activity. 5 Gold in Humans. Humans contain a mean of 0.35 μg of gold (0) per gram of dry tissue weight 16 which, according to calculations by Merchant, equates to 2.45 mg of gold in an average 70 kg man. 6 Blood gold concentrations in healthy human subjects have also been reported to be around 0 0.001 ppm, 17 with additional studies reporting small quantities of gold in hair (0.3 μg/g), skin (0.03 μg/g), and nails (0.17 μg/g). 18 20 Up to 0.8 μg of gold per dry weight has also been measured in fingers beneath gold wedding rings of normal individuals. 21 Interestingly, gold is also sometimes used in food in very minute quantities in pastries, chocolates, and even alcoholic beverages. 22 Gold Therapy. On the basis of the chemistry of gold, gold(I) is used as the main therapeutic agent as it is water soluble, is less reactive than gold(III) and is easily stabilized in a complex by the addition of ligands. Gold can be delivered to patients intravenously, intramuscularly, or orally with gold preparations specifically designed for each particular route of administration. Accordingly, gold taken orally needs to be lipid soluble for it to be absorbed within the gastrointestinal tract and will therefore have different physiochemical, pharmacokinetic, and toxicological properties compared to water soluble gold that is injected. 9,23 This is supported by experiments demonstrating only 1% of injectable gold is absorbed when given orally compared to 100% when given intramuscularly. 24 Although gold has been recently used as an anticancer and antimicrobial agent, 5 most of the studies on the efficacy, toxicity, and pharmacokinetics of gold preparations were previously performed in patients with RA who were treated with gold in the late 20th century. However, despite gold being used in clinical practice for several decades there is still considerable debate as to whether injectable or oral gold preparations are better for patients. 25 Initially, oral gold treatments that were developed in the 1980s, such as Auranofin, were thought to have improved pharmacokinetic profiles with less tissue retention, less toxicity, and reduced serum gold levels that were maintained for longer. 5 However, their clinical side effect profile and fear of long-term immune suppression have resulted in injectable compounds, such as gold sodium thiomalate, remaining the preferred gold drugs for RA treatment. 25 Gold Pharmacokinetics and Biodistribution. The bioavailability of gold in patients very much depends on the route of administration. While injectable gold compounds are fully absorbed with maximum levels attained after about 2 h, 26 only 20 25% of oral gold is absorbed. 23,24,27 Furthermore, intermittent dosing regimens of injectable gold result in fluctuating blood gold levels with high peak and low trough concentrations. 28 In contrast, oral gold preparations can be taken regularly and made with prolonged blood half-life preparations, resulting in a nearly constant concentration of gold for the duration of a patient’s treatment. However, with chronic daily oral administration the serum gold concentrations reaches a plateau, and in some cases, B dx.doi.org/10.1021/nl202559p |Nano Lett. XXXX, XXX, 000–000
Nano Letters PERSPECTIVE despite constant dosing, gradually starts to decline. 29 Various mechanisms have been put forward to explain this phenomenon including insufficient drug compliance, increased drug clearance, or an increased distribution volume (i.e., a shift from proteinbound gold to cell-bound gold). 29 Following absorption of gold, either from tissues or the gastrointestinal tract, approximately 95% is bound to albumin and/or globulin where it can remain within the plasma for several months. 4,30 Gold has also been found within the cellular compartment of blood, primarily in the erythrocyte fraction. 31,32 Here, gold has been shown to be within or attached to the membranes of red blood cells (RBCs), 24,33 with uptake dependent on either the amount of gold available for red cell precursors in the bone marrow or the gold binding capacity of plasma proteins. 32 Indeed, it has been shown that uptake into RBCs ceases after 48 h even though there is still considerable gold in the plasma, presumably as all the gold by this time is tightly bound to plasma proteins. As gold uptake into RBCs differs among people, being more pronounced in smokers, 34 this could explain the large variability in gold distribution seen among patients. Gold is widely distributed throughout the body with organs of the reticuloendothelial system, especially the lymph nodes, having the greatest affinity for this heavy metal. 16 The liver and bone marrow have each been shown to account for 25% of the total body gold burden with the skin and bone each accounting for 20%. 23 Furthermore, the exact form of gold in these locations remains unknown although it appears to be inactive as it remains detectable in tissue samples taken from patients who had been treatedwithgoldyearsearlier. 35 In general, gold has little affinity for keratinous tissue, 18 but it can accumulate in the skin dermis 36,37 during intravenous administration, with negligible levels recorded when gold is given orally. 28 At very high levels of intravenous administration, gold has also been shown to deposit in the cornea as detected by slit lamp examination. 38 Gold Metabolism and Excretion. Gold is primarily excreted in the urine and feces and although the rate of excretion varies considerably from patient to patient, the basic pattern remains the same. 30,36 Following intramuscular injection of gold, it has been shown that urinary excretion was greatest during the first day postinjection while fecal excretion was greatest during the middle of the week. 30 Although, the amount of gold excreted in the urine and feces increases as the amount of injected gold increases, the excretion rate was not directly proportional to the amount injected. 30 The high binding capacity of albumin for gold may explain the slow rate of gold clearance throughout the week following gold injection. When gold is given orally, 85 95% is excreted in feces and the remaining 5 15% in urine, regardless of dose. 27,28 The majority of gold recovered in the feces represents nonabsorbed gold, gold breakdown products, gold shed from mucosal cells to which it was adsorbed and a minor contribution from the biliary tract. 24,39 Once gold treatment is established, a dynamic equilibrium is set up in the body with gold moving between the blood, body stores, urine, and feces. Gold Toxicity. Any toxicity associated with gold depends on its oxidation state when given to patients. Metallic gold (gold(0)) is an extremely inert metal which is widely used throughout the world in both jewellery and prostheses. Indeed, most of the human population has had prolonged dermal contact with gold(0) in the form of jewelry, with only exceptionally rare cases of adverse reactions or allergic contact dermatitis. Furthermore, approximately half of the 1 billion people in the modern industrialized world carry dental prostheses made of gold with relatively few cases of oral lesions being reported despite the close prolonged contact of the metal with the oral mucosa. 6 However, gold(0) can, in very minute amounts, be converted to gold(I) by amino acids contained in sweat and saliva which can then be absorbed through the skin or gingival mucosa and later enter phagocytic and antigen presenting cells. 40 That notwithstanding, the metabolic impact of this is usually insufficient to evoke clinical symptoms. 6 Moreover, as gold(0) is readily available, has a very low toxicity profile, and can be made into a consistently small size and shape, it has been used as a delivery vehicle for gene therapy. 41 Indeed, microprojectile bombardment of cells with DNA on gold particles has been developed as an effective method of high frequency gene transfer with minimal damage to living cells. 42 Experiments injecting naked gold beads into the epidermis of pigs, whose skin is an excellent model for human skin, concluded that apart from acute impact physical effects, which resulted in mild transient dermal irritation, there were no direct toxicities or adverse effects on health, survival, clinical chemistry, or hematology values related to the gold beads. 6 Gold(I) is normally used as therapeutic agent in both injectable and oral preparations. The toxicities surrounding gold(I) have been primarily understood by examining patients treated with gold for RA; however frustratingly, serum and urine levels of gold have been of no value in predicting impending toxicity in patients. The most common toxicity associated with gold treatment is skin and mucous membrane hypersensitivity reactions, with nonspecific pruritic erythematous, macular, and papular rashes appearing first. Other rarer skin reactions include cheilitis, eosinophilia, chronic papular eruptions, contact sensitivity, erythema nodosum, allergic contact purpura, exfoliative dermatitis, and pityriasis rosea. 6 This diverse range of dermal reactions appears not to depend on the gold concentrations in the skin and rarely occur in patients who receive less than 250 mg of gold salts. 11 In fact, it is generally regarded that these reactions represent the balance between the total body burden of gold salts and the patient’s genetic and metabolic makeup. Management involves the cessation of gold therapy with most cases resolving within 3 months of onset depending on their extent and severity. The most common form of gold-induced dermatitis is nonallergic, since following clearance of the original eruption, patients can be restarted on gold treatment without developing further dermatitis. 43 In contrast, allergic contact dermatitis occurs at a lower incidence and represents an immune reactivity to gold which usually necessitates total cessation of gold therapy. 44 Diarrhea is also frequently associated with administration of gold complexes, but with a greater incidence when patients use oral gold preparations. 45 Less frequently, gold has been associated with nephrotoxicity as demonstrated by minor and transient proteinuria in people treated with injectable gold complexes. 3,46 Occasionally, this may progress to glomerulonephritis with nephritic syndrome although patients usually recover fully within a few months. 9,47 Hematological abnormalities can also be sometimes produced by gold complexes and include eosinophilia, thrombocytopenia, 9 and rarely aplastic anemia probably as a result of a direct inhibition of myelopoiesis. 48 Several other reports have also mentioned the rare consequences of using gold complexes including entercolitis with bloody diarrhea, 49,50 diffuse inflammatory lung reactions, 51 and neurotoxicity. 52 Gold therapy is not recommended during pregnancy, 53 as animal studies have shown it to be teratogenic. 54 Caution is also advised in the puerperium, despite conflicting reports as to whether significant absorption occurs in the infant, since gold can also be found in breast milk. 55 C dx.doi.org/10.1021/nl202559p |Nano Lett. 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Gold Nanoparticles - Department of Chemistry

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